pnas201107823 11320..11322


Profile of David M. Hillis

P
hilippe Padieu was called a mod-
ern-day Casanova. Women said
they were drawn to him for his
sweet personality and charm.

However, Padieu harbored a secret. In
2009, he was found guilty of aggravated
assault for purposefully infecting six
women with HIV and sentenced to 45
years in prison. Credit for Padieu’s guilty
verdict goes partly to David Hillis, an
evolutionary biologist at the University
of Texas at Austin.
Hillis, elected to the National Academy

of Sciences in 2008, has devoted his re-
search career to phylogeny, the study of
evolutionary relationships. His work tack-
les some of the greatest questions of evo-
lutionary biology: How do species arise?
How do genes diversify and acquire new
functions? How do pathogens evolve, and
how can that information be used to un-
derstand diseases? And ultimately, can we
reconstruct the complete Tree of Life and
use that information to help make pre-
dictions about biology?
Before the Padieu case, Hillis and col-

leagues had used phylogeny to determine
the degree of relatedness among HIV
carriers. However, in the Padieu case,
prosecutors needed to show that the HIV
traveled from Padieu to his victims, rather
than the other way around. HIV was
known to infect each host with billions of
virions. However, when the virus travels
from a source to recipient, a genetic bot-
tleneck occurs and typically only one of
those virions makes the jump into the new
host. Because the virus evolves rapidly,
Hillis’ team was able to show that six of
the samples were derived from the sev-
enth. In court, that seventh sample was
revealed as belonging to Padieu (1).

Amphibian Evolution
Much of Hillis’ early exposure to science
came through his father, an Air Force
physician and epidemiologist. Hillis was
born in Copenhagen, Denmark, but his
family later relocated to San Antonio,
TX. There, in the early 1960s, Hillis’ fa-
ther treated a veterinarian who had con-
tracted hepatitis from one of the chim-
panzees used in the US space program.
That case and other ones like it over-
turned the belief that chimps were im-
mune to the disease, suggesting instead
that chimps could be carriers. Un-
derstanding hepatitis’ mode of trans-
mission consumed the elder Hillis’
subsequent work, and the family re-
located to the Congo so he could study
chimpanzees in the wild. En route to
Africa, though, the Hillis’ belongings
were stolen, a strangely serendipitous
experience. “We had no toys. There were

no distractions like television or anything
like that. The primary way I had to en-
tertain myself was to run around the
jungles of Africa and catch lizards and
snakes and butterflies,” Hillis says.
That scientific curiosity stayed with

Hillis as the family fled the Congolese civil
war. The family later lived in Calcutta,
India, and then Baltimore, MD, where
both Hillis’ parents took up faculty posi-
tions at The Johns Hopkins University.
By high school, Hillis had grown intrigued
by reptiles and amphibians. “I became
fascinated with reptiles in Africa, where
I’d caught and kept lizards and learned
that many adults were scared of snakes,”
he recalls. “A little kid with a snake feels
powerful, I think, as many adults have
learned an unnatural fear of them.” As an
undergraduate, Hillis realized that am-
phibians were also ideal organisms for
studying how species diverge and evolve.
He graduated in 1980 with a degree in
biology from Baylor University in Waco,
TX, and entered a graduate biology pro-
gram at the University of Kansas in
Lawrence to study amphibian evolution.
At that time, phylogenies were largely

constructed based on the morphology of
organisms, by using such characteristics as
shape and size. However, Hillis realized
that much more information on evolu-
tionary relationships was encoded in ge-
nomes. Researchers were just beginning to
analyze chloroplast and DNA, passed

down through the maternal line. However,
both types of analyses had their short-
comings: chloroplast DNA analysis was
restricted to plants, and mtDNA evolves
so quickly that it was best suited for
reconstructing relatively recent di-
vergence events. So Hillis looked to nu-
clear ribosomal DNA, as well as nuclear-
encoded proteins, to reconstruct the
evolutionary history of amphibians. The
results revealed enormous hidden di-
versity among morphologically similar
amphibians (2, 3). Rather than throwing
out centuries of morphological work,
however, Hillis worked to integrate mo-
lecular and morphological studies of
phylogeny (4).
Soon Hillis turned his attention to how

individual genes evolve and diversify. For
instance, when Hillis and his colleagues
studied the evolution of the ZFY gene,
then thought to trigger male development
in mammals, they found that the gene was
unrelated to sex determination in reptiles
(5). “It was one of the first indications
that the ZFY gene was not actually the sex
determination gene, as it was initially
thought to be,” Hillis says. Soon after, the
actual sex-determining gene of mammals,
SRY, was discovered.
Hillis’ work in frogs and reptiles made

clear that phylogenies could reveal how
life on Earth evolved. Rather than look at
single species, Hillis now devotes much of
his time to modeling evolution on com-
puters and coming up with ways to detect
evolutionary patterns in enormous data-
sets. Although his early interest in science
may have come from his father, Hillis
gives credit for his more recent work to
his mother, a biostatistician.

Watching Evolution
Hillis’ shift toward statistical and com-
putational approaches to evolution began
when he accepted a faculty position at the
University of Texas at Austin, where he
now works. There, he met his colleague
Jim Bull, initially a skeptic of phyloge-
netic analysis. “He didn’t think there were
any convincing studies of the accuracy of
phylogenetic methods,” Hillis says. Bull
had reason to doubt. By that point in the
late 1980s, phylogenetic analysis was
growing in popularity, but its accuracy
remained in question. Because much
evolution occurs over lengthy time scales,
it usually cannot be observed directly.
Morphological change can be examined
in the fossil record, but molecular

David M. Hillis.

This is a Profile of a recently elected member of the Na-
tional Academy of Sciences to accompany the member’s
Inaugural Article on page 21242 in issue 50 of volume107.

11320–11322 | PNAS | July 12, 2011 | vol. 108 | no. 28 www.pnas.org/cgi/doi/10.1073/pnas.1107823108

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changes—increasingly the basis for phy-
logenetic studies—are not preserved
in fossils.
Hillis was convinced he could get Bull

to come around. So they made a deal.
“The stakes were high,” Hillis jokes. “We
bet a quarter.” For a convincing case,
Hillis and Bull needed to find a species
that evolved fast enough to be observable
in real time—one that could grow, re-
produce, and accumulate mutations in
minutes rather than millennia. The two
researchers settled on T7 bacteriophage,
a virus that doubles its population in less
than 15 minutes. They started with a sin-
gle ancestral stock and let it reproduce
for hundreds of generations, separating
out colonies at predetermined intervals.
To encourage rapid evolution, the prog-
eny were exposed to a chemical that
promotes mutations during viral
replication (6).
Hillis, who was blinded to the experi-

mental setup to avoid biasing the results,
mapped the genomes of the evolved ex-
perimental viruses and used five phylo-
genetic methods to reconstruct the
phage’s evolutionary history. When the
blinded labels were decoded, Bull agreed
that the estimated trees provided an ac-
curate picture of the actual evolutionary
history. Moreover, the ancestral genomes
at each branching point in the phylogeny
had been reconstructed with greater than
98% accuracy. The pair soon devised
ways to test the validity of the phyloge-
netic methods under more difficult con-
ditions, such as subjecting divergent
lineages to vastly different rates of evo-
lution or similar selective conditions
(7, 8). Even then, the phylogenetic
methods could account for the evolu-
tionary changes.
That meant that phylogenetic methods

could help researchers piece together
evolutionary history, including the de-
tailed reconstruction of ancient gene
sequences. “A lot of people have ex-
tended that work to look at the gene se-
quences of extinct organisms extending
back to the common ancestor of life,”
Hillis says.
Looking back to the dawn of life, al-

though, presents other challenges. Unlike
the experimental viral trees, the evolu-
tionary relationships in most phylogenetic
trees cannot be observed directly. So how
can biologists assess the accuracy of an-
cient phylogenies? In a series of pio-
neering papers, Hillis and his colleagues
showed how statistical resampling ap-
proaches and Monte Carlo simulations,
which predict the probabilities of certain
outcomes based on prespecified models,
can be used to assess confidence in a given
phylogenetic tree. The researchers tested
the reliability of these statistical ap-
proaches on experiments with simulated

phylogenies as well as the bacteriophages
they had studied in the laboratory (9, 10).
In the mid-1990s, biologists began

tackling phylogenies with hundreds of
species. Many people were skeptical that
such large phylogenies—which Hillis says
contain more potential solutions than
the number of fundamental atomic par-
ticles in the universe—could be recon-
structed accurately. One of the larger
trees at the time was produced by Pam
and Doug Soltis, evolutionary biologists
who now work at the University of Flor-
ida in Gainesville. The duo had recon-
structed the evolutionary relationships
among 228 species of flowering plants by
comparing their ribosomal RNA genes
(11). However, some researchers were
unconvinced by the Soltises’ findings, ar-
guing that efforts to recreate the evolu-
tionary histories of just a handful of
species required the analysis of many
more genes—and that the same principle
should hold true for larger data sets, like
the flowering plants.
To resolve the dispute, Hillis simulated

the evolution of the ribosomal RNA genes
on a computer. Expecting to find that
the Soltises needed more data, Hillis was
surprised to discover that denser sampling
of species generated more realistic phy-
logenetic trees. “Analyzing more genes
was helpful, but analyzing more species
was critical for phylogenetic accuracy,”
Hillis says. “It was great news for the
Soltises and for the field as a whole” (12).
Densely sampled trees provided more

accurate reconstructions of evolutionary
history and allowed researchers to develop
more detailed and accurate models of
DNA evolution (13, 14). As a result, Hillis
says, “many researchers are now tackling
problems with thousands of species.”
Leading the charge is the National Sci-
ence Foundation and its ambitious Tree
of Life program, which aims to generate
a phylogenetic tree connecting all life
forms on Earth (15–17).
Estimates, however, suggest that the

Earth contains approximately 9 million
species, making it difficult to view the
complete Tree of Life in 2D space, Hillis
says. So Hillis and his colleagues devel-
oped new techniques to visualize complex
phylogenetic information (18). Among
other solutions, they designed a circular
tree with 3,000 clickable points, each
representing a different taxonomic group.
Clicking a point opens up another 3,000
points, for a total of 9 million points—or
species. “That way, the whole tree of life
can be represented in two layers,”
Hillis says.
An early version of that circular tree of

life has now entered pop culture: some
of Hillis’ graduate students have tattooed
the design on their backs and a giant Tree
of Life mural currently graces the en-

tranceway of the biology building at
University of Texas’ Austin campus. Next
to the location of humans, the tree has
a “you are here” sign. “At the beginning
of the semester, there are always a lot of
mystified students looking at it saying
‘I don’t understand. . . is this a map of
campus?’” Hillis says.

Evolution Matters
The theoretical groundwork laid, Hillis
became interested in applying phyloge-
netic methods to answer questions about
the molecular processes underlying evo-
lution. Hillis first ventured into the study
of HIV transmission following a high-
profile case in the early 1990s in which an
HIV-positive dentist in Florida was ac-
cused of transmitting the virus to several
patients. After evaluating blood samples
from infected individuals, the Centers for
Disease Control determined that the HIV
strains in the doctor and his patients were
related. Hillis was asked to review the
results of this new methodology. The
methods the Centers for Disease Control
used were sound, Hillis says, but the
case never went to trial because the dentist
died in the interim.
It took another high-profile case for the

phylogenetic analysis of HIV to make
its way into US courtrooms. In the late
1990s, a physician stood accused of in-
tentionally injecting his ex-girlfriend with
an HIV-infected blood sample from an
unwitting patient. The prosecution thus
needed to show that the HIV samples
between the patient and ex-girlfriend were
related (19).
The science behind showing the re-

latedness of HIV strains is straight out of
the phylogeny textbook, Hillis says. As
noted, when HIV passes from source to
recipient, typically only one virion makes
the jump. That virion then diversifies
rapidly inside its new host. To determine
relatedness between samples, researchers
take many samples of the virus from the
victim and defendant and reconstruct the
phylogeny of the virus as it mutates and
evolves into different strains. The re-
sultant trees either support or rule out
hypotheses about the virus’s transmission
from person to person.
In the case of the physician’s girlfriend,

her HIV sequences supported the hy-
pothesis that she contracted HIV from
the physician’s patient. The final step was
for the courts to determine whether to
permit these HIV phylogenies as evi-
dence in the courtroom. Hillis was called
in as an expert witness to explain phylo-
genetic analysis to the court. The judge
agreed to admit the phylogenetic evi-
dence—together with all the other evi-
dence about means, motive, and
opportunity—and the jury found the
physician guilty of attempted murder.

Gupta PNAS | July 12, 2011 | vol. 108 | no. 28 | 11321

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Hillis’ Inaugural Article (1) pushes fo-
rensic applications of phylogeny a step
further by showing how phylogenies can
also provide information on the direction
of transmission. Because of the genetic
bottleneck that occurs at the point of
transmission, a recipient’s tree is expected
to be nested within the source’s tree,
Hillis says. In the case of Phillipe Padieu,
and a very similar case from Washington
state, information about the direction of
transmission was integral to the estab-
lishment of the men’s guilt.
However, if the science behind phylo-

genetic analysis of HIV is straightforward,
the ethics are not. Practiced incorrectly,
phylogenetic analysis could become a way
of criminalizing those with HIV, Hillis
cautions. Fear of criminal liability could
also prevent people from getting tested,
which could be especially problematic in
AIDS-ridden countries. Rather, Hillis
says, before applying phylogenetic analysis
to transmission questions, it is funda-
mental to first have evidence of criminal
intent, as well as a clear a priori hypothesis
to test.

Science Education
Hillis’ latest endeavor may turn out to be
the most complicated. As with his re-
search, Hillis says he takes his “role as an

educator very seriously.” He penned his
first textbook, a how-to manual for re-
constructing phylogenies, in 1990 (20–23).
More recently, Hillis has become an
outspoken critic of efforts to weaken the
teaching of evolution in schools, a partic-
ularly heated debate in Hillis’ home state
of Texas. Part of informing students
about the importance of evolution, Hillis
says, is making biology more accessible
and relevant to students. “The contents of
college textbooks generally are accurate,”
he says, “but I find it depressing how
boring most of them are.”
In the past few years, Hillis has auth-

ored two introductory biology textbooks,
Life: The Science of Biology, and Principles
of Life, to address that shortcoming (24–
26). Thanks to that work and his efforts to
advise the Texas State Board of Educa-
tion on the science curriculum, Hillis won
the Stand Up For Science award in 2009
(from the Texas Freedom Network) and
the Friend of Darwin award in 2010
(from the National Center for Science
Education).
Hillis applies and enjoys evolution on

a personal level as well. The proud owner
of the aptly named Double Helix Ranch in
Texas, Hillis has been studying his pop-
ulation of Texas Longhorn cattle to un-
derstand their evolutionary roots.

According to historic accounts, Christo-
pher Columbus brought cattle from
Europe to the Caribbean in the late 1400s.
From there, the cattle were taken to
Mexico and the American Southwest,
where they escaped and formed feral
herds. Over the centuries, the cattle
evolved longer horns, which served as
defense against predators. With the cattle
genome now complete, Hillis and his
students are comparing breeds of do-
mestic cattle from region to region to
reconstruct their population histories.
As with his other work, Hillis’ research

into the cattle has shifted from mere sci-
entific curiosity to a search for practical
applications. Texas Longhorns have many
genes that confer disease resistance, fe-
cundity, longevity, and ease of birthing,
all of which are important in creating
hardy breeds of grass-fed, free-range
cattle, he says.
Evolution, says Hillis, helps answer both

sweeping questions (what is the origin of
life?) and ordinary ones (how does one
create better cows?). Hillis’ motivation for
studying evolution is simple: “I like
thinking about the common ancestors
that I share with the cotton fibers in my
shirt,” he says.

Sujata Gupta, Freelance Science Writer

1. Scaduto DI, et al. (2010) Source identification in two
criminal cases using phylogenetic analysis of HIV-1 DNA
sequences. Proc Natl Acad Sci USA 107:21242–21247.

2. Hillis DM, Frost JS, Wright DA (1983) Phylogeny and
biogeography of the Rana pipiens complex: A bio-
chemical evaluation. Syst Zool 32:132–143.

3. Hillis DM, Davis SK (1986) Evolution of ribosomal DNA:
Fifty million years of recorded history in the frog ge-
nus Rana. Evolution 40:1275–1288.

4. Hillis DM (1987) Molecular versus morphological ap-
proaches to systematics. Annu Rev Ecol Syst 18:23–42.

5. Bull JJ, Hillis DM, O’Steen S (1988) Mammalian ZFY
sequences exist in reptiles regardless of sex-deter-
mining mechanism. Science 242:567–569.

6. Hillis DM, Bull JJ, White ME, Badgett MR, Molineux IJ
(1992) Experimental phylogenetics: generation of
a known phylogeny. Science 255:589–592.

7. Bull JJ, et al. (1997) Exceptional convergent evolution
in a virus. Genetics 147:1497–1507.

8. Cunningham CW, Zhu H, Hillis DM (1998) Best-fit
maximum likelihood models for phylogenetic in-
ference: Empirical tests with known phylogenies.
Evolution 52:978–987.

9. Hillis DM, Bull JJ (1993) An empirical test of boot-
strapping as a method for assessing confidence in
phylogenetic analysis. Syst Biol 42:182–192.

10. Hillis DM, Huelsenbeck JP, Cunningham CW (1994)
Application and accuracy of molecular phylogenies.
Science 264:671–677.

11. Soltis DE, et al. (1997) Angiosperm phylogeny inferred
from 18S ribosomal DNA sequences. Ann Mo Bot Gard
84:1–49.

12. Hillis DM (1996) Inferring complex phylogenies. Na-
ture 383:130–131.

13. Zwickl DJ, Hillis DM (2002) Increased taxon sampling
greatly reduces phylogenetic error. Syst Biol 51:
588–598.

14. Heath TA, Zwickl DJ, Kim J, Hillis DM (2008) Taxon
sampling affects inferences of macroevolutionary
processes from phylogenetic trees. Syst Biol 57:
160–166.

15. National Science Foundation (2011) Assembling the
Tree of Life (ATOL) ATOL update: 3/14/11. Available at
http://www.nsf.gov/funding/pgm_summ.jsp?pims_id=
5129&org=EF. Accessed April 27, 2011.

16. Halanych KM, et al. (1995) Evidence from 18S ribo-
somal DNA that the lophophorates are protostome
animals. Science 267:1641–1643.

17. Hillis DM (2005) Health applications of the Tree of Life.
Evolutionary Science and Society: Educating a New
Generation, eds. Cracraft J, Bybee R (Biological Scien-
ces Curriculum Study, Colorado Springs, CO), pp
139–144.

18. Hillis DM, Heath TA, St John K (2005) Analysis and vi-
sualization of tree space. Syst Biol 54:471–482.

19. Metzker ML, et al. (2002) Molecular evidence of HIV-1
transmission in a criminal case. Proc Natl Acad Sci USA
99:14292–14297.

20. Hillis DM, Moritz C (1990) Molecular Systematics (Si-
nauer, Sunderland, MA).

21. Hillis DM, Mable BK, Larson A, Davis SK, Zimmer EA
(1996) Hillis DM, Mable BK, Moritz CNucleic acids IV:
Sequencing and cloning. Molecular Systematics, eds.
Hillis DM, Mable BK, Moritz C (Sinauer, Sunderland,
MA), 2nd Ed, pp 321–381.

22. Swofford DL, Olsen GJ, Waddell PJ, Hillis DM (1996)
Phylogenetic inference. Molecular Systematics, eds.
Hillis DM, Mable BK, Moritz C (Sinauer, Sunderland,
Massachusetts), 2nd Ed, pp 407–514.

23. Hillis DM, Mable BK, Moritz C (1996) Applications of
molecular systematics and the future of the field.
Molecular Systematics, eds. Hillis DM, Mable BK,
Moritz C (Sinauer, Sunderland, MA), 2nd Ed, pp
515–543.

24. Hillis DM, Sadava D, Heller HC, Price MV (2010) Prin-
ciples of Life. Sinauer Associates and W. H (Sinauer,
Sunderland, MA).

25. Sadava D, Heller HC, Orians GH, Purves WK, Hillis DM
(2006) Life: The Science of Biology (Sinauer, Sunderland,
MA), 8th Ed.

26. Sadava D, Hillis DM, Heller HC, Berenbaum M (2009)
Life: The Science of Biology (Sinauer, Sunderland, MA),
9th Ed.

11322 | www.pnas.org/cgi/doi/10.1073/pnas.1107823108 Gupta

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http://www.nsf.gov/funding/pgm_summ.jsp?pims_id=5129&org=EF
http://www.nsf.gov/funding/pgm_summ.jsp?pims_id=5129&org=EF